PROJECT SUMMARY Psychotic disorders account for more than 10% of mental-health-related disease burden in the United States, but it remains difficult to predict who will develop a psychotic disorder, how their illness will progress, and how they will respond to available treatments. Recent findings suggest promise for genetic markers for psychotic illnesses, but these tools are imprecise, limiting their utility for basic research and clinical application. This K08 application outlines a research and training program that will support the applicant's development towards an NIH-funded, independent research career investigating the genetic liabilities for serious mental illness. The activities outlined in this application build on the candidate's clinical and quantitative background, and through training exercises set in a resource-rich environment, facilitate the development of expertise in 1) scientific communication and responsible conduct of research; 2) statistical genetics, 3) genetics of psychotic disorders, and 4) translational research for evaluating genetic markers for clinical applications. The aim of the research outlined in this proposal is to validate a novel method of identifying polygenic risk for psychotic disorders that takes account of overlapping symptoms and common genetic vulnerabilities. This approach aims to improve the precision of polygenic risk scores. This method will be applied in an ethnically diverse sample of 30,000 individuals with psychotic disorders, identifying polygenic risk scores for both general and specific facets of psychotic symptomatology. The resulting risk scores will be validated in pooled analysis of nine longitudinal cohort studies, comprising 1,785 cases. Risk scores will be tested as predictors of psychosis onset, diagnosis, symptom trajectory, psychosocial outcomes, and treatment response. If the proposed research succeeds in identifying genetic correlates of specific dimensions of psychotic disorders that predict these important health outcomes, it will have important implications for etiological research, as it may help to identify targets for intervention. The findings would also have significance for clinical translational research, as genetic markers have potential application as aids in diagnosis and prognosis.